Where is that one guideline providing all regulatory considerations for virtual trials? The one document that clearly describes all requirements without much room for interpretation? Unfortunately this Hitchhiker’s Guide to the Galaxy of Virtual Trials does not exist. Yet.
The regulation of virtual trials is still in its infancy and only just starting to catch up with the development and demands in the field of human research.
However, while there is not one well established guidance that everyone can adhere to globally, Health Authorities actively support virtual studies and digital tools and there are some existing initiatives, regulations and guidance documents, scattered like puzzle pieces, that can be taken into account, if a study includes virtual aspects. So let’s take a look on relevant areas and a few of the (missing) pieces.
For the purpose of this article, the information will mainly focus on considerations concerning ICH-GCP, United States (US) / U.S. Food and Drug Administration (FDA) and European Union (EU) / European Medicines Agency (EMA) as the information is best established for these, but other regulatory bodies have also started to pick up on the industry demand and developments in the digital realm and guidance on certain areas may already be available, locally, or become available soon.
Patient Rights, Safety and Wellbeing
Patients are an integral part of clinical research and still for a long time they have often been primarily regarded as a resource or asset to be used (“subject”) instead of acknowledging their central and essential role as active participants. In recent years this mindset has started changing, also due to patient advocacy groups actively engaging with the industry and regulators. The field is beginning to look at a more patient-centric approach to clinical research and the smart use of virtual technologies is thought to alleviate patient burden and allow research to integrate more seamlessly into the patient’s life without major disruption of their daily routines.
The FDA and EMA are both promoting a more patient-centric approach to clinical study participation and data collection. The agencies have jointly created a workgroup on patient engagement called the FDA/EMA Patient Engagement Cluster(1) in order to share best practices involving patients along drug and biologic regulatory lifecycles. The 21st Century Cures Act(2) in the United States was designed to help accelerate medical product development and bring new innovations and advances to patients who need them faster and more efficiently and the FDA’s Center for Drug Evaluation and Research (CDER) is promoting Patient Focused Drug Development as a systematic approach to help ensure that patients’ experiences, perspectives, needs, and priorities are captured and meaningfully incorporated into drug development and evaluation(3).
FDA have further indicated that they see the benefits of the appropriate use of technology in clinical trials. They were amongst the first to publish on use of electronic informed consent (eConsent) in clinical investigations, providing IRBs, Investigators and Sponsors with guidance on how to provide trial information to subjects and capture informed consent(4). In the EU no central guidance on the use of eConsent has been published. As national laws of the EU member states govern acceptability of (electronic and/or digital) signatures, guidance will need to be sought on the national level, e.g. the joint MHRA and HRA statement on eConsent(5).
But not only regulators are supporting the deployment of virtual technologies in trial design, several non-regulatory initiatives are also trying to establish recommendations on the use of virtual tools. An important example is the Clinical Trial Transformation Initiative (CTTI) comprising more than 80 organizations from across the clinical trial enterprise, including representatives of government agencies, industry representatives, patient advocacy groups, professional societies, investigator groups, academic institutions, and other interested parties. The CTTI has published several recommendations(6) regarding virtual studies, e.g. on decentralized trials and the use of mobile technologies. The recommendations currently mainly focus on the US, nonetheless, many considerations could also be applied in other regulatory environments.
However, while the use of virtual technologies enable a more patient-specific approach to clinical research, they also pose a potential threat to the patients’ rights, safety and well-being, which need to be appropriately assessed and prevented.
Adequate training of investigators and study personnel on the protocol, systems and GCP is an important factor to ensure patient safety and data accuracy. Virtual trials with a decentralized or hybrid design can include the use of mobile health care providers (HCPs) (e.g. nurses, physicians), telemedicine or visits to the patient’s general practitioner (GP) or a local laboratory close to the patient’s home. For all personnel which contribute to the study, adequate training must be ensured and for all technical facilities, documentation of accreditation/certification needs to be provided to meet basic GCP requirements(8). In the classic clinical trial design, delegation of tasks would also have to clearly be documented, e.g. in a delegation log. Depending on the size of the study, the effort in training and documentation could be enormous, impacting feasibility and costs. When using mobile HCP vendors with experience in clinical trials, training and documentation requirements are likely easier to meet, but it might not be feasible or practicable to ensure full protocol and GCP training for every single GP and other personnel involved in assessment and sample collection in local facilities and have delegation of tasks documented on a delegation log; or to collect accreditation / documentation for each patient’s local laboratory. It could be arguable whether reduced training and documentation requirements for local GPs and laboratories could be acceptable, however and unfortunately, there is currently no regulatory guidance available which discusses the potential for reduced requirements and until this is available it must be assumed that full documentation requirements apply.
Ethically and legally the challenges also include data ownership and sharing, consent requirements, privacy and data security(14). The use of virtual technology in human research often includes the use of wearables (i.e. sensors and/or software applications on smartphones and tablets that can collect health-related data remotely). In the EU, the General Data Protection Regulation (GDPR) covers all data generated by wearable devices or apps in the medical context. A clearly defined purpose for the data use, consent for data reuse and sharing is required and patients are allowed to withdraw their consent at any time. In the US however, there is a distinction between consumer-grade and medical devices and data ownership is regulated differently. Data obtained by medical devices are subject to HIPAA and therefore require patient consent for collection and sharing, whereas data obtained by consumer-grade devices can be shared in a de-identified and aggregate manner without explicit stipulation concerning who will have access to the data.
Virtual systems are susceptible to security breaches and adequate security controls must be implemented to ensure the patients’ privacy remains warranted. The US National Institute of Standards and Technologies have published the latest draft revision of their guidance on Security and Privacy Controls for Information Systems and Organizations, detailing new families of privacy and security controls that can be used as the basis of design and audit (NIST Special Publication 800-53, Revision 5 – Final Public Draft) for virtual technologies(7).
Virtual technologies, such as wearables, can be used to collect various health data (e.g. vital sign and cardiac monitoring) and assess the health status of a patient on a more frequent basis and remotely (in contrast to only punctual assessments during on-site visits) and can therefore be used to assess efficacy and safety data and endpoints in a more holistic approach(14). However, devices or systems with a high error rate for the intended assessment or use of systems or methods not clinically validated could potentially result in a safety risk for patients, e.g. when important health signals are not detected, or render collected data unreliable or “unfit-for-purpose”; which consequently would expose patients to unnecessary risks and discomforts. Adequate validation, both analytical and clinical, is therefore imperative, if virtual technology is employed in clinical trials.
Integrity, accuracy and reliability of Virtual Clinical Research Data
As digital tools have been a part of clinical research for a long time now, with increasing contribution every year, several guidance documents on system validation as well as reliability and acceptability of electronic data, records and signatures are available in clinical research and related fields.
With the second revision of the ICH-GCP guideline, validation of computerized systems has become a basic requirement(8). In the US the 21 CFR part 11(9) established procedures and controls for Electronic Records and Electronic Signatures, which continue to be applicable for virtual technologies in clinical trials. Several supportive guidance documents to 21 CFR part 11 have been published by the FDA, e.g. on Electronic Source Data in Clinical Investigations(10). In the EU there is no regulation governing validation of computerized systems, however the guidance document EudraLex Vol. 4 Good Manufacturing Practice (GMP) Annex 11 – Computerized systems(11), although initially developed for product manufacturing ensuring product quality, has now widely been adopted as standard in the Good Clinical Practice (GCP) and Good Laboratory Practice (GLP) sections of the industry. The GMP Q&A section on Data Integrity(12) can also be helpful when considering data risk, criticality, life-cycle and more. Specifically for GCP a reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials was published by the EMA’s GCP Inspectors Working Group, outlining their current opinion on the use of electronic data capture in clinical trials and on related inspections(13).
The use of wearables for virtual data collection is specifically critical, as those systems play an essential role in the practicability of virtual trials. However, at this time there is substantial doubt and confusion in the industry about the appropriate use and specifically the validation of the individual specific technologies for the context of use (COU). Izmailova et al. (2018) suggest a fit-for-purpose approach with appropriate analytical and clinical validation in the respective COU(14). EMA, while aware of the development and sharing their experience and expectations that mobile health technology must be linked to a meaningful clinical benefit(15), had long been pending to provide the industry with clear guidance on their expectations on validation of wearables and acceptability of the data collected with them in the context of clinical trials with pharmaceutical products. Triggered by a specific request from Novartis, EMA published a Qualification Opinion for the use of technology to capture trial source data electronically(16). This Qualification opinion is intended to give information about the regulatory acceptability to use an eSource Direct Data Capture (DDC) in clinical trials conducted to support a Marketing Authorisation Application for a medicine. It focuses on the processes and systems which may be needed to ensure robust direct data entry.
Devices and software used for medical purpose (e.g. diagnosis, prevention, monitoring, treatment or alleviation of disease) are classified as a medical device in the EU, which have to undergo a conformity assessment, confirmed by the CE (Conformité Européenne) mark, to demonstrate that they meet legal requirements to ensure they are safe and perform as intended(17). Not every wearable device or software used in clinical trials will fall under the regulation of medical devices, but when designing a trial with the intend to involve EU countries, the purpose of the wearable / software to be used and their status in the EU (conformity assessment passed or not) need to be carefully considered.
As we have seen, the regulatory picture of virtual trials is currently still missing a few puzzle pieces, but as virtual technologies and their use in human research are evolving, the regulatory field is following suit. The International Medical Device Regulators Forum (IMDRF)(18), a voluntary group of medical device regulators from around the world, have come together to discuss and accelerate international medical device regulatory harmonization and are developing standards relevant to the use of virtual technology.
Industry stakeholders, regulators and other initiatives are constantly contributing to the ongoing development of technologies and their use in the context of human research and we can look forward for many more developments in the near future. So let’s keep on puzzling and add to the bigger picture of virtual trials.
Sources and relevant links:
- FDA/EMA Patient Engagement Cluster: https://www.fda.gov/patients/learn-about-fda-patient-engagement/fda-and-european-medicines-agency-patient-engagement-cluster
- 21st Century Cures Act: https://www.fda.gov/regulatory-information/selected-amendments-fdc-act/21st-century-cures-act
- CDER Patient-Focused Drug Development: https://www.fda.gov/drugs/development-approval-process-drugs/cder-patient-focused-drug-development
- FDA - Use of Electronic Informed Consent in Clinical Investigations – Questions and Answers: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-electronic-informed-consent-clinical-investigations-questions-and-answers
- HRA and MHRA joint statement on seeking and documenting consent using electronic methods (eConsent): https://www.hra.nhs.uk/about-us/news-updates/hra-and-mhra-publish-joint-statement-seeking-and-documenting-consent-using-electronic-methods-econsent/
- CTTI recommendations: https://www.ctti-clinicaltrials.org/briefing-room/recommendations
- NIST Special Publication 800-53, Revision 5 – Final Public Draft: https://csrc.nist.gov/publications/detail/sp/800-53/rev-5/draft
- ICH-GCP R2: https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf
- 21 CRF part 11: http://academy.gmp-compliance.org/guidemgr/files/CFR_2018/CFR-2018-TITLE21-VOL1-PART11.PDF
- Guidance for Industry - Electronic Source Data in Clinical Investigations https://www.fda.gov/regulatory-information/search-fda-guidance-documents/electronic-source-data-clinical-investigations
- EudraLex Vol. 4 Good Manufacturing Practice (GMP) Annex 11 – Computerized systems https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/annex11_01-2011_en.pdf
- EMA Q&A GMP data integrity: https://www.ema.europa.eu/en/human-regulatory/research-development/compliance/good-manufacturing-practice/guidance-good-manufacturing-practice-good-distribution-practice-questions-answers#data-integrity-(new-august-2016)-section
- Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/reflection-paper-expectations-electronic-source-data-data-transcribed-electronic-data-collection_en.pdf
- Ismailova et al., Wearable Devices in Clinical Trials: Hype and Hypothesis, Clin Pharmacol Ther. 2018 Jul; 104(1): 42–52. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032822/)
- EMA experience on mHealth technology, 17Apr2018: https://www.ema.europa.eu/en/documents/presentation/presentation-ema-experience-mhealth-technology-emas-pcwp-hcpwp-joint-meeting-francesca-cerreta_en.pdf
- EMA - eSource Direct Data Capture (DDC) qualification opinion https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/qualification-opinion-esource-direct-data-capture-ddc_en.pdf
- Regulation (EU) 2017/745: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A32017R0745
- International Medical Device Regulators Forum: http://www.imdrf.org/